Obesity and its fatal sequelae are among the most prevalent and challenging morbidities confronting the medical profession in the 21^^ century. Obesity leads to insulin resistance, hyperglycemia, and dyslipidemia. To lower blood glucose, the pancreas produces excess insulin which stimulates the liver to convert excess glucose to FAs and TGs. The increased FAs produce two potentially fatal sequelae: 1) elevated plasma lipids and atherosclerosis, leading to death from myocardial infarction or stroke; and 2) fatty liver, which can lead to death from cirrhosis and liver failure. The burden of these FA-related complications is enormous. More than half of the deaths in obese type 2 diabetics are attributable to cardiovascular disease (1). Moreover, more than one-third of the US population accumulates excess TGs in liver (2) a condition known as non-alcoholic fatty liver disease (NAFLD), which accounts for 10% of the liver transplants in the US (3). If we are to combat the deadly consequences of excess FA synthesis, we must understand the regulatory factors that trigger this response. Our Program Project Grant made an important start with two discoveries: 1) that SREBP-lc is the key protein mediating insulin stimulation of FA synthesis in the liver;and 2) that an SREBP-lc target gene, MIG12, encodes a protein that markedly stimulates the activity of acetyl-CoA carboxylase (ACC), the first committed enzyme in FA synthesis. If we successfully complete the studies outlined in Research Project 3, we will have laid the basis for a new strategy to prevent the excess synthesis of FAs, and ameliorate the fatal consequences of obesity and diabetes.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Program Project Review Committee (HLBP)
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